Page 24 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-13]

Identification of inhibitors of Bcl-2 family protein-protein

interaction by combining the BRET screening platform with

virtual screening

Iseul Park¹, Haeng Ran Seo², Kideok Kim¹, Honggun Lee¹, David Shum¹, Inhee Choi³, Jiho Kim¹˙*

¹Screening Discovery Platform, Institut Pasteur Korea, Seongnam-si 13488, South Korea, ²Cancer Biology

Laboratory, Institut Pasteur Korea, Seongnam-si 13488, South Korea, ³Medicinal Chemistry, Institut Pasteur Korea,
Seongnam-si 13488, South Korea

Bcl-2 family proteins play key roles in tumor initiation, progression, and resistance to therapy. Therefore, the protein-

protein interactions (PPIs) between the pro-survival proteins B-cell lymphoma (Bcl)-2, and Bcl-xL and the pro-
apoptotic proteins Bax, and Bak could be attractive therapeutic targets for anti-cancer drug discovery. Here, we

found new small molecules, BIP-A1001 and BIP-A2001 that modulated Bak/Bax and Bcl-xL interactions by combining
the Nanoluc/YFP-based bioluminescence resonance energy transfer (BRET) assay with structure based virtual

screening. In addition, we chose compounds with similar structures to BIP-A1001 and BIP-A2001 and tested their
inhibitory effects using the BRET assay as a dose-response function. The results indicated that identifying

compounds that inhibit interactions between Bak/Bax and Bcl-xL could be a promising approach to enhance cancer
therapy.